Primary open-angle glaucoma (POAG) is an intraocular pressure (IOP) related, progressive optic neuropathy that ultimately leads to blindness. Permanent visual field loss from POAG is a condition of public health significance worldwide. The etiology of POAG is poorly understood and primary prevention is not possible. Elevated intraocular pressure (IOP) is a modifiable risk factor, however, many individuals have IOP elevation without optic nerve disease , and at least 33% of POAG cases have progressive retinal ganglion cell loss despite IOP measurements in the normal range, a condition defined as normal-tension glaucoma (NTG). Preventative or neuro-protective therapies for glaucoma are not yet available and little is known about the molecular events that influence susceptibility to glaucomatous optic nerve degeneration. The overall goal of our research is to elucidate the pathogenesis of POAG allowing for implementation of effective screening and prevention strategies and development of novel therapies. POAG has significant heritability and recent genome-wide association studies, including our NEIGHBORHOOD GWAS, have identified 30 POAG loci defined by common genomic variants. However, in addition to common variants the complex POAG genetic architecture is likely to also include contributions from rare coding variants that implicate specific genes in disease pathogenicity, as has been discovered for other complex traits. Large-scale studies of rare coding variation in glaucoma populations have not yet been done. The focus of this competing renewal is to comprehensively examine the contributions of coding variation to POAG and the HTG and NTG subgroups with a primary goal of identifying novel therapeutic targets and specifically those with neuro-protective potential. For the next funding period we propose the following specific aims: 1) Obtain high quality whole exome sequence (WES) data for POAG cases and controls using state-of-the-art sequencing and robust variant calling and annotation pipelines; 2) Assess contribution of rare coding variants to POAG and to NTG and HTG subgroups; and 3) Build a web-based platform for data analysis, data-sharing and communication.